1,3-dithiol compounds

ABSTRACT

A 1,3-dithiol compound represented by the formula:   WHEREIN R and R&#39;&#39; represent each hydrogen, lower alkyl, aryl or ar(lower)alkyl and R&#39;&#39;&#39;&#39; represents hydroxy, lower alkoxy, (lower)alkylthio, aryloxy, arylthio, ar(lower)alkoxy, ar(lower)alkylthio or (mono- or disubstituted)aminothiocarbonylthio, being useful as antibacterial, antifungal, anti-inflammatory, insecticidal, miticidal agents or their intermediates, is prepared from a 1,3-di-thiol-2-ylidenammonium salt in 3 steps.

United States Patent Takamizawa et al.

1,3-DITHIOL COMPOUNDS Inventors: Akira 'lakamizawa, Ibaraki; Kentarol-lirai, Kyoto, both of Japan Shionogi 8: Co., Ltd., Higashi-ku, Osaka,Japan Filed: Feb. 11, 1970 Appl. No.: [0,620

Assignee:

Foreign Application Priority Data Feb. 14, 1969 Japan ..44/lll65 U.S.Cl. ..260/247.1, 260/268 H, 260/293.68, 260/327 M, 424/248, 424/267,424/277 Int. Cl ..A6lk 27/00, C07d 87/46, C07d 71/00 Field of Search..260/327 M, 247.1, 293.68

References Cited OTHER PUBLICATIONS Campaigne et al., J.O.C. 29: 2877-2881 (October, 1964).

Primary Examiner-Henry R. Jiles Assistant Examiner-Cecilia M. ShurkoAttorney-Wenderoth, Lind and Ponack [57] ABSTRACT A 1,3-dithiol compoundrepresented by the formula:

wherein R and R represent each hydrogen, lower alkyl, aryl orar(lower)alkyl and R represents hydroxy, lower alkoxy, (lower)alkyithio,aryloxy, arylthio, ar(lower)alkoxy, ar(lower)alkylthio or (monoordi-substituted)aminothiocarbonylthio, being useful as antibacterial,antifungal, anti-inflammatory, insecticidal, miticidal agents or theirintermediates, is prepared from a l,3-di-thiol-2-yliden-ammonium salt in3 steps.

21 Claims, No Drawings l ,3-DITHIOL COMPOUNDS The present inventionrelates to l,3-dithiol compounds. In particular, this invention relatesto l,3-dithiol compounds represented by the formula:

wherein R and R represent each hydrogen, lower alkyl, aryl orar(lower)alkyl and R" represents hydroxy, lower alkoxy.(lower)-alkylthio aryloxy, arylthio, ar(lower)alkoxy, ar(lower)alkylthioor (monoor di-substituted)aminodithiocarbonylthio which are useful asantibacterial, antifungal, anti-inflammatory, insecticidal, miticidalagents or their intermediates. The present invention also relates to theproduction of the said compounds (1).

Accordingly, a basic object of the present invention is to embody novel1,3-dithiol compounds (I). Another object of the invention is to embody1,3-dithiol compounds (I) useful as antibacterial, antifungal,anti-inflammatory, insecticidal, miticidal agents or theirintermediates. A further object of this invention is to embody a processfor the production of the l,3- dithiol compounds (I). These and otherobjects will be apparent to those conversant with the appurtenant artfrom the following description of the general class of compounds and theseveral specific examples and methods of obtaining them presented.

According to the present invention, the said 1,3-dithiol compounds (I)can be prepared from a 1,3-dithiol-2-ylidenammonium salt in 3 steps, asshown in the following schema:

Step A S in 1 R, s \R2 (III) 1 Step B R RIS (IV) 1 l Step C wherein Rand R represent each hydrogen, lower alkyl (e.g. n-butyl, isopropyl,methyl, ethyl), aryl (e.g. phenyl, 2- naphthyl, p-chloro-phenyl,p-tolyl, p-methoxyphenyl), or ar(lower)alkyl (e.g. benzyl, phenethyl,p-methoxyphenyl-npropyl), R and R represent each lower alkyl (e.g.ethyl, isobutyl, methyl, n-pentyl), aryl (e.g. phenyl, l-naphthyl,ptolyl, o-methoxyphenyl), ar(lower)alkyl (e.g. phenethyl, benzyl,m-chlorophenyl-n-butyl) or heterocyclic ring in combination withinclusion of the nitrogen atom (e.g. morpholino, piperidino orpiperazino), X and Y represent each an anion of a strong acid (e.g.hydrochloric acid, sulfuric acid, nitric acid, perchloric acid,fluoboric acid, hydrobromic acid, hydroiodic acid, phosphoric acid,rhodanic acid, p-toluenesulfonic acid, picric acid, nitrobenzoic acid,halogenoacetic acid) and R" represents hydroxy, lower alkoxy (e.g.isopropoxy, ethoxy, methoxy, n-pentyl-oxy), (lower)alkylthio (e.g.ethylthio, n-pentylthio, methylthio, isobutylthio), aryloxy (e.g.2-naphthyloxy, l-naphthyloxy, phenoxy, chlorophenoxy, p-nitrophenoxy),arylthio (e.g. p-tolylthio, 2-

p-tolyloxy, o-

naphthylthio, phenylthio, p-chlorophenylthio), ar(lower)- aloxy (e.g.benzyloxy, phenethyloxy, Z-naphthyl-n-propyloxy,p-methoxy-phenethyloxy), ar(lower)alkylthio (e.g. benzylthio,phenethylthio, p-chlorobenzylthio, l-naphthyl-npropylthio) or (mono-ordi-substituted)aminothiocarbonylthio (e.g. morpholinothiocarbonylthio,piperidinothiocarbonylthio; methylphenylaminocarbonylthio,dimethylaminothiocarbonylthio, ethylaminothiocarbonylthio,diethylaminothiocarbonylthio). The Steps A, B and C are explained moreconcretely as follows:

STEP A Step A is effected by reducing the l,3-dithiol-ammonium salt (ll)with a metallic hydride complex (e.g. lithium aluminum hydride, sodiumborohydride, lithium borohydride) in an inert solvent (e.g. water,methanol, ethanol, tetrahydrofuran, dioxane, ether, pyridine) in therange of temperature from ice cooling below room temperature to theboiling point of the solvent. The starting l,3-dithiol-ammonium salt(II) involves illustratively;

N-( 4-phenyl-l ,3-dithiol-2-yliden)-piperidinium hydrogen sulfate,

N-( 4-phenyll ,3-dithiol-2-yliden)-morpholinium fluoborate,

N-( 4-phenyl-l ,3-dithiol-2-yliden )-morpholinium hydrogen sulfate,

N-(4-phenyl-1,3-dithiol-2-yliden)-N-methylbenzylammonium fluoborate,

N-( 4-phenyll ,3-dithiol-2-yliden )-N-dimethylammonium perchlorate,

N-[4-(p-nitrophenyl)-l,3dithiol-2-yliden1-piperidinium fluo-borate,

N-[4-(p-nitrophenyl)-1,3-dithiol-2-yliden]-piperidinium hydrogensulfate,

N-[4-( p-bromophenyl l ,3-dithiol-2-yliden ]-piperidinium fluoborate,

N-[4-(p-tolyl)- l ,3-dithiol-2-yliden]-piperidinium hydrogen sulfate,and

N-[ 4-( p-methoxyphenyl )-l ,3-dithiol-2-yliden -piperidinium hydrogensulfate.

Thus, there is obtained the 2-(di-substituted)amino-l,3- dithiol (III)successfully.

STEP B Step B is effected by reacting the2-(di-substituted)aminol,3-dithiol '(lII) obtained in Step A with astrong acid (e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid,phosphoric acid, rhodanic acid, p-toluenesulfonic acid, picric acid,pnitrobenzoic acid, monochloroacetic acid, trifluoroacetic acid) in aninert solvent. The starting 2-(di-substituted)aminol ,B-dithiol (Ill)involves illustratively;

2-piperidino-4-phenyl-l ,3-dithiol,

2-morpholino-4-phenyll ,3-dithiol,

2-methylbenzylamino-4-phenyll ,3-dithiol,

2-dimethylamino-4-phenyll ,3-dithiol,

2-piperidino-4-( p-nitrophenyl l 3-dithiol,

2-piperidino-4-(p-bromophenyl)-1 ,3-dithiol,

2-piperidino-4-( p-tolyl)- l ,3-dithiol, and

2-piperidino-4( p-methoxyphenyl)- l ,3-dithiol.

The present reaction may be effected favorably in the range oftemperature from room temperature to the boiling point of the solvent.Examples of the solvent are water, methanol, ethanol, monoglyme,diglyme, ether, dioxane, tetrahydrofuran and pyridine, and a suitablesolvent may be selected according to sorts of the starting compound(III) and the strong acid. Thus, there is obtained the 1,3-dithioliumsalt )lV) in a good yield.

STEP C Step C is efiected by reacting the 2,3-dithiolium salt (IV)obtained in Step B with a nucleophilic reagent. The starting1,3-dithiolium salt (IV) involves illustratively;

4-phenyll ,3-dithiolium perchlorate,

' benzyl alcohol, phenethyl alcohol, Z-naphthyl-n-propyl alcohol,p-methoxyphenethyl alcohol), alkali alcoxide (e.g. sodium n-propoxide,potassium methoxide, sodium ethoxide, lithium n-pentyloxide, potassiumisopropoxide, potassium benzyloxide, sodium phenethoxide, sodium2-naphthyl-npropoxide), mercaptan (e.g. ethyl mercaptan, isobutylmercaptan, methyl mercaptan, isopentylmercaptan, benzyl mercaptan,phenethyl mercaptan, p-chlorobenzyl mercaptan, lnaphthyl-n-propylmercaptan), alkali mercaptide (e.g. ethyl sodium mercaptide, isobutylpotassium mercaptide, phenethyl lithium mercaptide, p-methoxyphe-nethylpotassium mercaptide), alkali phenolates (e.g. sodium phenolate,potassium pnitrophenolate, sodium -2-naphtholate, lithiump-methoxyphenolate), alkali thiophenolates (e.g. sodium thiophenolate,potassium p-chlorothiophenolate, lithium thio-l-naphtholate, sodiump-nitrothiophenolate) and alkali (monoordi-substituted)-aminodithiocarbamate (e.g. sodiumdimethylaminodithiocarbamate, potassiummethylphenylaminodithiocarbamate, sodium piperidinodithiocarbamate,potassium morpholinodithiocarbamate, sodiumdiisopropylaminodithiocarbamate, potassium ylaminodithiocarbamate,sodium dibenzylaminodithiocarbamate, potassiummethylbenzylaminodithiocarbamate), the said alkali salts being possiblysubstituted for alkali earth salts (e.g. calcium or barium salts),ammonium salts or salts of an organic base (e.g. morpholine, piperidine,methylbenzylamine, pyrrolidine). The reaction of this step may befavorably effected in the range of temperature from room temperature tothe boiling point of the solvent used, when needed, in the presence of abase (e.g. sodium hydroxide, potassium carbonate, sodium bicarbonate,pyridine, triethylamine, dimethylaniline). Examples of the solvent arealcohols (e.g. methanol, ethanol, isopropanol), ethers (e.g.tetrahydrofuran, diglyme, monoglyme, ether, dioxane), acetone,chloroform and hydrocarbons (e.g. benzene, toluene), and an excess ofthe nucleophilic reagent may be used in lieu of the solvent.

The thus-obtained l,3-dithiol compounds (I) involve illustratively;

2-methoxy-4-phenyl-1,3-dithiol,

2-methoxy-(p-tolyl)-1,3-dithiol,

2-methoxy-4-( p-bromophenyl)-l ,3-dithiol,

2-methoxy-4-( p-chlorophenyl)- l ,3-dithiol,

2-methoxy-4-(p-nitrophenyl)-1,3-dithiol,

2-methoxy-4,5-diphenyll ,3-dithiol,

2-ethoxy-4,5-diphenyll ,3-dithiol,

2-phenylthio-4-phenyll ,3-dithiol,

2-hydroxy-4-phenyl-l ,3-dithiol,

2-morpholinothiocarbonylthio-4-phenyl-l ,3-dithiol,

2-piperidinothiocarbonylthio-4-phenyll ,3-dithiol,

2-dimethylaminothiocarbonylthio-4-phenyll ,3-dithiol,

2 dimethylaminothiocarbonylthio-4-( p-chlorophenyD-l ,3- dithiol, v

Z-dimethylaminothiocarbonylthio-4-(p-hydroxyphenyl)- 1,3-dithiol,

2-dimethylarninothiocarbonylthio-4-(p-methoxyphenyl)- l ,3-dithiol,

2-dimethylaminothiocarbonylthio-4-( p-tolyl)-l ,3-dithiol,

2-( 2-naphthyl)thio-4-phenyl-l ,B-dithiol,

2-( 2-naphthoxy)-4-phenyll ,3-dithiol,

2-(p-tolylthio)-4-phenyl-l ,S-dithiol, and

2- dimethylaminothiocarbonylthio-4-( p-nitrophenyl)- l ,3- dithiol.

diphen- These l,3-dithiol compounds (I) are useful as antibacterial,antifungal, anti-inflammatory, insecticidal, miticidal agents or theirintermediates, and so they can be used broadly in the field ofmedicinals, animal's drugs or agriculturalchemicals. For instance,2-phenylthio-4-phenyl-l,3-dithiol and 2-dimethylaminothiocarbonylthio-4-phenyl-l,3-dithiol showed about 5 to 10mcyml of the minimum inhibitory concentrations in the agar dilutionmethod against Trichophyton rubrum, Trichophyton ferrugineum,Trichophyton purpureum, Trichophyton mentagrophytes and Epidermophytonfluccosum. Still, 2-dimethylaminothiocarbonylthio-4-phenyl-1,3- dithiolshowed 10 mcg [ml of the minimum inhibitory concentration in the tubedilution method against Mycobacterium tuberculosis H37 Rv and was about1.5 times more potent in the preventive activity against Piriculariaoryzae in comparison with PCBA (i.e. pentachlorobenzyl alcohol).Further, 2- methoxy-4-phenyl-l,3-dithiol showed powerful insecticidalactivity against Musca domestica and miticidal activity againstTetranychus telarius.

Presently-preferred and practical embodiments of the present inventionare illustratively shown in the following examples. Temperatures are setforth in degrees centigrade.

EXAMPLE 1.

a. To a suspension of N-(4-phenyl-l,3-dithiol-2-yliden)- piperidiniumfluoborate 1.0 g) in ethanol (10 ml), there is added sodium borohydride(0.3 g'), and the resultant mixture is stirred at room temperature for 2hours. The reaction mixture is combined with a small amount of acetoneand concentrated under reduced pressure. The residue is crystallizedfrom water to give colorless needles. The needles are collected c. To ahot solution of 4-phenyl-l,3-dithiolium perchlorate (3.0 g) in methanolml), there is added 10 percentaqueous solution (30 ml) of sodiumcarbonate, and the resultant mixture is concentrated under reducedpressure. The residue is combined with water, and the precipitatedcrystals are collected by filtration and recrystallized from diluteethanol to give 2-methoxy-4-phenyl-l,3-dithiol (2.2 g) as colorlessneedles melting at 61 C. The yield is 97 percent. Similarly, there areobtained the following compounds.

1. 2-Methoxy-4-(pmethoxyphenyl)- l ,3-dithiol, 50-52 C.

2. 2-Methoxy-4-(p-tolyl)-1,3-dithiol, oil.

3. 2-Methoxy-4-(p-bromophenyl)- l ,3-dithiol, 'm.p. 4344 4.2-Methoxy-4-(pchlorophenyl)-l,3-dithiol, m.p. 32-34. C

5. 2-Methoxy-4-(p-nitrophenyl)-l ,3-dithiol, m.p. l l6l 17 C. a

6. 2-Methoxy-4,5-diphenyl-l ,3-dithiol, m.p. 6768 C. 7.2-Ethoxy-4,5-diphenyl-l,3-dithiol, m.p. 7880 C.

EXAMPLE 2.

a. N-( 4-Phenyl-l ,3-dithiol 2-yliden )-morpholinium i fluoborate istreated with sodium borohydride in ethanol to' give2-morpholino-4-phenyl-1,3-dithiol as crystals melting at 82-83 C. Theyield is 93 percent.

b. 2-Morpholino-4-phenyl-1,3-dithiol is reacted with cone. sulfuric acidto give 4-phenyl-l ,3-dithiolium hydrogen sulfate as crystals melting at180 C. The yield is 94 percent.

c. To a sodium thiophenolate solution prepared by adding thiophenol mg)to a solution of metallic sodium (22 mg) in anhydrous ether (8 ml),there is added 4-phenyl-l,3- dithiolium hydrogen sulfate (200 mg), andthe resultant mixture is refluxed for an hour. The reaction mixture isconcentrated to remove the solvent, and the residue is crystallized frompetroleum benzene to give 2-phenylthio-4-phenyl-l,3- dithiol (134 mg) ascrystals melting at 81 to 82 C. The yield is 66 percent. Similarly,there are obtained the following compounds.

I. 2-( p-Tolylthio)-4-phenyll ,S-dithiol, m.p. 93-94 C.

2. 2-(Z-Naphthylthio)-4-phenyl-l,3-dithiol, m.p. 129-130 C.

3. 2-(2-Naphthyloxy)-4-phenyl-1,3-dithiol, oil.

EXAMPLE 3.

To a suspension of 4-phenyl-l,3-dithiolium hydrogen sulfate (200 mg) inether (30 ml), there is added water ml), and the resultant mixture isshaken with ether. The ethereal layer is separated, dried andconcentrated to remove the ether. Thus, there is obtained2-hydroxy-4-phenyl-l,3- dithiol (100 mg) as light brown prisms meltingat 90 to 92 C. The yield is 70 percent.

EXAMPLE 4.

To a suspension of 4-phenyl-l,3-dithiolium hydrogen sulfate (100 mg) inacetone (100 ml), there is added morpholine morpholinocarbodithioate(150 mg), and the resultant mixture is refluxed for minutes. Thereaction mixture is concentrated to remove the solvent, and the residueis combined with water. The mixture is shaken with ether. The ethereallayer is dried and the solvent is evaporated to give 2-morpholinothiocarbonylthio-4-phenyl-l ,3-dithiol (130 mg) as crystalsmelting at 119 to 120 C. The yield is 96 percent. Similarly, there areobtained the following compounds.

1 2-Piperidinothiocarbonylthio-4-phenyl-1,3-dithiol, m.p. 1 l9-120 C.

2. Z-Dimethylaminothiocarbonylthio-4-phenyl-l,3-dithiol, m.p. 78-79 C.

3. Z-Dimethylaminothiocarbonylthio-4-(p-chlorophenyl)- 1,3-dithiol, m.p.107-108 C.

4. 2-Dimethylaminothiocarbonylthio-4-(p-hydroxyphenyl)- l,3-dithiol,m.p. 1 l4-l 15 C.

5. 2-Dimethylaminothiocarbonylthio-4-(p-methoxypheny1)-1,3-dithiol,m.p.l l21 14 C.

6. 2-Dimethylaminothiocarbonylthio-4-(p-tolyl)- l ,3- dithiol, m.p. 9699C.

7. 2-Dimethylaminothiocarbonylthio-4-(p-niti'ophenyl)- 1,3-dithiol, m.p.l34-l 36 C.

What is claimed is:

l. A 1,3-dithiol compound represented by the formula:

wherein R and R represent each hydrogen, lower alkyl, phenyl,Z-naphthyl, p-chlorophenyl, p-tolyl p-methoxyphenyl benzyl, phenethyl,or p-methoxyphenyl-n-propyl and R represents hydroxy, lower alkoxy,(lower)alkyl-thio, 2- naphthyloxy, l-naphthyloxy, phenoxy, p-tolyloxy,ochlorophenoxy, p-nitrophenox p-tolylthio, Z-naphthylthio, phenylthio,p-chlorophenylthio benzyloxy, phenylethyloxy, 2- naphthyl-n-propyloxy,p-methoxy-phenethyloxy, benzylthio, phenylethylthio, p-chlorobenzylthio,l'naphthyl-n-propylthio morpholinothiocarbonylthio,piperidino-thiocarbonylthio, methylphenylaminothiocarbonylthio,dimethylamino-thiocarbonylthio, ethylaminothiocarbonylthio, ordiethylaminothiocarbonylthio.

2. A compound according to claim 1, in which R is phenyl, R is hydrogenand R is methoxy.

3. A compound according to claim 1, in which R is p-tolyl, R is hydrogenand R" is methoxy.

4. A compound according to claim 1, in which R is pbromophenyl, R ishydrogen and R" is methoxy.

5. A compound according to claim 1, in which R is pchlorophenyl, R ishydrogen and R" is methoxy.

6. A compound according to claim 1, in which R is pnitrophenyl, R ishydrogen and R" is methoxy.

7. A compound according to claim 1, in which R and R are each phenyl andR is methoxy.

8. A compound according to claim 1, in which R and R are each phenyl andR is ethoxy.

9. A compound according to claim 1, in which R is phenyl, R is hydrogenand R is phenylthio.

10. A compound according to claim 1, in which R is phenyl, R is hydrogenand R" is hydroxy.

11. A compound according to claim 1, in which R is phenyl, R is hydrogenand R" is morpholinothiocarbonylthio.

12. A compound according to claim 1, in which R is phenyl, R is hydrogenand R is piperidinothiocarbonylthio.

13. A compound according to claim 1, in which R is phenyl, R is hydrogenand R is dimethylaminothiocarbonylthio.

14. A compound according to claim 1, in which R is pchlorophenyl, R ishydrogen and R is dimethylaminothiocarbonylthio.

15. A compound according to claim 1, in which R is phydroxyphenyl, R ishydrogen and R" is dimethylaminothiocarbonyl-thio.

16. A compound according to claim 1, in which R is pmethoxyphenyl, R ishydrogen and R is dimethylaminothiocarbonyl-thio.

17. A compound according to claim 1, in which R is p-tolyl, R ishydrogen and R" is dimethylaminothiocarbonylthio.

18. A compound according to claim 1, in which R is phenyl,

R is hydrogen and R" is Z-naphthylthio.

2. A compound according to claim 1, in which R is phenyl, R'' ishydrogen and R'''' is methoxy.
 3. A compound according to claim 1, inwhich R is p-tolyl, R'' is hydrogen and R'''' is methoxy.
 4. A compoundaccording to claim 1, in which R is p-bromophenyl, R'' is hydrogen andR'''' is methoxy.
 5. A compound according to claim 1, in which R isp-chlorophenyl, R'' is hydrogen and R'''' is methoxy.
 6. A compoundaccording to claim 1, in which R is p-nitrophenyl, R'' is hydrogen andR'''' is methoxy.
 7. A compound according to claim 1, in which R and R''are each phenyl and R'''' is methoxy.
 8. A compound according to claim1, in which R and R'' are each phenyl and R'''' is ethoxy.
 9. A compoundaccording to claim 1, in which R is phenyl, R'' is hydrogen and R'''' isphenylthio.
 10. A compound according to claim 1, in which R is phenyl,R'' is hydrogen and R'''' is hydroxy.
 11. A compound according to claim1, in which R is phenyl, R'' is hydrogen and R'''' ismorpholinothiocarbonylthio.
 12. A compound according to claim 1, inwhich R is phenyl, R'' is hydrogen and R'''' ispiperidinothiocarbonylthio.
 13. A compound according to claim 1, inwhich R is phenyl, R'' is hydrogen and R'''' isdimethylaminothiocarbonylthio.
 14. A compound according to claim 1, inwhich R is p-chlorophenyl, R'' is hydrogen and R'''' isdimethylaminothiocarbonylthio.
 15. A compound according to claim 1, inwhich R is p-hydroxyphenyl, R'' is hydrogen and R'''' isdimethylaminothiocarbonyl-thio.
 16. A compound according to claim 1, inwhich R is p-methoxyphenyl, R'' is hydrogen and R'''' isdimethylaminothiocarbonyl-thio.
 17. A compound according to claim 1, inwhich R is p-tolyl, R'' is hydrogen and R'''' isdimethylaminothiocarbonylthio.
 18. A compound according to claim 1, inwhich R is phenyl, R'' is hydrogen and R'''' is 2-naphthylthio.
 19. Acompound according to claim 1, in which R is phenyl, R'' is hydrogen andR'''' is 2-naphthyloxy.
 20. A compound according to claim 1, in which Ris phenyl. R'' is hydrogen and R'''' is p-tolylthio.
 21. A compoundaccording to claim 1, in which R is p-nitrophenyl, R'' is hydrogen andR'''' is dimethylaminothiocarbonylthio.